The invention relates to the use of purine derivatives in the manufacture of a medicament intended for the treatment of pathologies in which an imbalance between cell division and apoptosis is involved and more particularly in which excessive apoptosis is the cause of the pathology.
It also relates to some of these purine derivatives.
The pathologies in which an imbalance between cell division and apoptosis is involved are in particular chronic lymphoid leukemia and kidney diseases, such as polycystic kidney disease.
Chronic lymphoid leukemia, CLL, is a heterogeneous group of diseases characterized by the accumulation of CD5+ monoclonal B cells in the blood, bone marrow and hematopoietic organs.
It is a disease in which the monoclonal B cells undergo no or little natural apoptosis (cell death) and comprise a small contingent of B cells involved in the cell cycle. In this sense, this disease is a disease rather different from the diseases in which an excessive proliferation, which is not stopped, of the monoclonal cells is observed, in which the monoclonal cells are highly involved in the cell cycle and in which the resistance to apoptosis (cell death) constitutes a phenomenon of secondary pathogenicity.
CLL is commonly classified into separate categories, including B-cell chronic lymphoid leukemia and T-cell chronic lymphoid leukemia. The term “CLL” is commonly understood to mean B-cell chronic lymphoid leukemia (B-CLL).
B-cell chronic lymphoid leukemia, known as B-CLL, is a disease of the B lymphocyte responsible for the accumulation of B lymphocytes of lymphocytic morphology, expressing membrane antigens characteristic of the disease, such as the CD5 and CD23 molecules, in the blood, causing hyperlymphocytosis, in the bone marrow, causing bone marrow failure, and in the lymph nodes, causing polyadenopathy.
B-CLL has been characterized as a single biological entity with a variable progressive nature.
The Binet prognosis classification makes it possible to arrange the profile of progression of the disease into three stages A, B and C.
Among the subjects in stage A of the disease, 41% will progress towards stages B and C. Among the biological parameters, the lymphocyte doubling time of less than 6 months, a rise in the level of soluble CD23 or a rise in the activity of serum thymidine kinase are considered as indicating poor prognosis. The fully identified genetic parameters of poor prognosis include the unmutated forms of the disease (immunoglobulin heavy chain gene in the germinal position on 14q32), deletion abnormalities of the 11q and 17p chromosomes or additional chromosomal abnormalities of 12q+ type. The patients who are carriers of B-CLL and who express these biological characters have a short progression time: thus, 50% of the unmutated patients have progressed in 24 months; 50% of the patients exhibiting a 17p−, an 11q− or a 12q+ have progressed at 15 months. If patients of stage A express these biological criteria for seriousness, the patients of stage B and C should benefit from an active therapeutic attitude.
Although current treatments bring about remissions of the disease, all the patients relapse and there currently exists a consensus in stating that CLL remains an incurable disease.
The real question which is posed today is that of defining, in stage A of the disease, the patients who exhibit a biological potential to progress to a serious state.
The best first-line treatment for B-CLL remains to be defined.
Purine analogs, in particular fludarabine, remain by far the most studied in B-CLL. Fludarabine alone induces a better overall level of response than the use of multidrug therapies comprising alkylating agents and a corticotherapy. Fludarabine induces more complete hematologic remission (7 to 40%) than multidrug therapies of CHOP or CAP (chloraminophene) type.
Despite the better response observed with fludarabine, the benefit observed with regard to overall survival remains marginal. Current therapeutic endeavors are directed at the combinations of fludarabine with conventional chemotherapy, for example fludarabine plus cyclophosphamide, in particular in the resistant forms of the disease. Life expectancy is only 12 months in patients resistant to fludarabine. Nevertheless, the toxicity of the treatment, in particular hematologic toxicity, is increased with these combinations.
Infection is observed in 50% of the patients treated with a combination of fludarabine and cyclophosphamide. Documented sepsis or pneumopathy is observed during the treatment in 25% of the patients treated, undocumented fever and/or hospitalization in 25% of the others.
A therapeutic revolution was achieved by the advent of therapeutic antibodies. In B-CLL, two therapeutic antibodies have emerged: rituximab and alemtuzumab. In B-CLL, the activity of rituximab is handicapped by the low expression of the target, the CD20 antigen, on the B lymphocyte of CLL. Rituximab is deployed in B-CLL in synergy with purine analogs and/or cyclophosphamide (overall response of 59% observed with the fludarabine/cyclophosphamide/rituximab combination in patients resistant to fludarabine, including only 5% of complete response).
The activity of alemtuzumab, directed against an antigen expressed on the leukocyctes and the leukemic B lymphocytes of CLL, with a very heterogeneous membrane density of the antigen, is handicapped by its high immunosuppressive activity and the high incidence of reactivations of cytomegalic infections and opportunist infections during or after treatment: the antibody exhibits a high T immunosuppressive activity. The hematologic response to alemtuzumab is 33%; the antibody is capable of destroying clonal B lymphcytes in the blood and the bone marrow but have little effect in the lymph nodes. These points limit the use of the antibody in this indication. Radioimmunotherapy with anti-CD20 coupled to yytrium-90 (Zevalin) induces a low percentage of remission in B-CLL and is responsible for significant myelosuppression.
U.S. Pat. No. 6,812,232 describes purine analogs similar to those of the invention for their activity in inhibiting cell proliferation. In point of fact, in CLL, excessive cell proliferation has stopped.
Patent application WO2005/002584 provides, for its part, for the use of roscovitine, preferably in its (R) absolute configuration, in the treatment of chronic lymphoid leukemia and more particularly of B-cell chronic lymphoid leukemia.
Roscovitine is a Purine Having the Following Formula:

In point of fact, it has now been discovered that roscovitine derivatives have a much higher activity than roscovitine in the treatment of pathologies in which an imbalance between cell division and apoptosis is involved and that they also have, in some cases, a better solubility than roscovitine.